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CaMKII mediates Ang‐II induced vascular smooth muscle cell hypertrophy by a pathway involving HDAC4/MEF2
Author(s) -
Li Hui,
Li Weiwei,
Gupta Arun,
Anderson Mark E.,
Grumbach Isabella M
Publication year - 2009
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.23.1_supplement.637.8
Subject(s) - hdac4 , mef2 , phosphorylation , muscle hypertrophy , chemistry , angiotensin ii , endocrinology , medicine , transcription factor , microbiology and biotechnology , vascular smooth muscle , biology , receptor , regulation of gene expression , biochemistry , gene , smooth muscle , histone methyltransferase , enhancer
The calcium/calmodulin‐dependent kinase II has been implicated in VSM growth and is activated by Ang‐II. Ang‐II activates the HDAC4/MEF2 dependent gene transcription which is important in muscle growth and hypertrophy. CaMKII specifically phosphorylates HDAC4 S467,632. We assessed the hypothesis that CaMKII mediates Ang‐II induced smooth muscle hypertrophy by a pathway involving HDAC4/MEF2. Methods and Results The medial hypertrophy induced by Ang‐II over 10 days in C57Bl/6 mice was significantly reduced when the CaMKII inhibitor KN93 was given daily i.p. Infection of rat aortic smooth muscle cells with adenovirus expressing CaMKIIδ2 resulted in a 108% increase in 3 H‐Leucine uptake with Ang‐II compared to 50% (p<0.05) increase in controls, whereas overexpression of the CaMKII peptide inhibitor CaMKIIN resulted in a 14 % increase. The phosphorylation of HDAC4 in response to Ang‐II was increased with the overexpression of CaMKIIδ2. CaMKII overexpression resulted in increased nuclear export of HDAC4, MEF2‐promoter activity and nucleoprotein complex formation in EMSA. HDAC4 overexpression led to decreased MEF2‐promoter activity and hypertrophy in response to Ang‐II. The dominant negative mutant HDAC4 S467,632A abrogated the activation. Conclusion CaMKII mediates Ang‐II induced VSM hypertrophy by derepressing HDAC4 and activating MEF2. Supported by: AHA, Carver Trust.